A bone fracture is a break or crack in a bone, with complete or incomplete disruption of the continuity of a bone, epiphyseal plate or articular surface. A bone fracture is caused mostly by some type of trauma to a bone. This trauma might occur as a result of a motor vehicle accident, an accident in a workplace, physical abuse, repetitive stress such as exercise, heavy lifting, etc. Normal, everyday activities can cause bone fractures in people with diseases that weaken the bones, such as osteoporosis, bone cancer, or metabolic abnormalities. According to fracture line (line along epiphyseal ends generated upon fracture), bone fractures are classified into fissured fractures, greenstick fractures, transverse fractures, oblique fractures, spiral fractures, segmental fractures, comminuted fractures, avulsion fractures, compression fractures, depressed fractures, etc.
Generally, upon a bone fracture, injury of blood vessels occurs, incurring partial hemorrhage and blood clots. In addition, the bone matrix around a fracture region is broken down or ruptured, with the death of osteocytes. During a fracture healing process, hence, the blood clots and the injured osteocytes and bone matrix are removed by macrophages while osteoprogenitor cells of the perilsteum and endosteum around the fracture region actively proliferate to form cellular tissue around the fracture region and are then integrated with the fracture region. In the connective tissue of the fracture region, either a bone tissue arises by endochondral ossification from a small cartilage fragment or an immature bone is formed by intramembranous ossification. Accordingly, intramembranous ossification from mesenchymal tissue and endochondral ossification are observed concurrently in the connective tissue of a fracture region. The trabecula of the immature bone irregularly formed in this way temporarily connects ends of the fractured bone fragments, resulting in the formation of a bony callus. The woven bone of the bony callus formed in the fracture region is gradually resorbed as the healing process progresses, and undergoes rearrangement resulting in the development of lamellar bone.
As a rule, fracture healing is largely divided into three phases: inflammatory phase, bone reparative phase, and remodeling phase.
In the inflammatory phase, inflammatory responses occur since tissues around a fracture region are injured and hematoma fills the fracture gap.
In the bone reparative phase, the hematoma is removed from the fracture gap and substituted with granulation tissue while soft callus is formed. According to the osteogenesis mechanism, two processes proceed concurrently: endochondral ossification, in which the soft callus is remodeled into hard callus, and fibrous/intramembranous ossification, in which a new bone is formed by osteogenic cells.
In the remodeling phase, newly formed bone tissue is extended over a long period of time by the orchestrated action of osteoclastic bone resorption and osteoblastic bone formation, with the correction of bone distortions and the reinforcement of bone defects.
During the remodeling phase, patients with a bone fracture conduct their lives without great difficulty because the newly formed bone has become hard to some extent, but the nascent bone tissue in the reparative phase is not hard enough for patients to live their daily lives without difficulty. In addition, the reparative phase is long. Thus, it is clinically important for a fracture curative to have the function of shortening the reparative phase as well as regenerating a fractured bone into a complete bone by promoting the complex fracture healing process.
There are various promoters for fracture healing. Peptides having physiologically active functions, such as bone morphogenic proteins (BMPs) and transforming growth factors (TGFs), are found to be involved in the fracture healing process (Proc. Natl. Acad. Sci., USA, vol. 87, pp. 2220-2224 (1989)). Also, it has been studied that an increase in intracellular cyclic AMP level by use of a phosphodiesterase (PDE) inhibitor can lead to an increase in bone mass. For example, it is reported that mice, into which the general PDE inhibitor pentoxipylline or the selective PDE4 inhibitor rolipram had been subcutaneously injected every day, were observed to have the vertebrate and femur increased in bone mineral density, and showed hyperplasia of cortical bones (Bone, vol. 27., 6th edition, pp. 811-817 (2000)).
As mentioned above, attention has long been paid to osteogenesis and fracture healing, and extensive studies on fracture healing processes have been conducted from various points of view, including genetic factors, adolescent influence, hematopoietic effect, fixture effect, bone grafts, other healing promoting factors, etc. (Kawamura, M and Urist MR., Clin. Orthop., 236, 240-248, 1988).
Fracture healing requires a significant period of time and patients with osteoporosis tend to suffer more from bone fractures according to the increase of an aged population. Falling short of the expectation of usefulness in fracture healing, currently available therapeutic agents for the treatment of osteoporosis, such as calcium, estrogen, calcitonin, active vitamin D, bisphosphonate, etc., are found only to lower the risk of fracture by obstructing the decrease of bone density, but to have no function of joining fractured bones or generating bone tissues. The pathogenic mechanism of osteoporosis can be explained by a subtle bone matrix resulting from long maintenance of negative bone homeostasis due to genetic or constitutional predispositions, stagnant osteogenesis with normal bone resorption, and increased bone resorption with normal osteogenesis. The therapeutic agents for the treatment of osteoporosis are, therefore, ineffective for the treatment of bone fracture because the healing mechanism is quite different between fractures and osteoporosis.
Due to the mechanism difference between fractures and osteoporosis, anti-osteoporotic agents, having a function of inhibiting bone resorption, may obstruct bone formation, thereby actually retarding the fracture healing process. For example, incadronate disodium, a bisphosphonate agent, is reported to retard fracture healing in the femurs of rats administered therewith (Li C et al., J. Bone Miner Res. 2001 March; 16(3):429-36). Also there is a report describing that whereas the pretreatment with incardronate has no influence on fracture healing until 16 weeks after a bone fracture, continuous treatment with incardronate increases bony callus, but results in the retardation of the remodeling process (Li J et al., J. Bone Miner Res. 1999 June; 14(6):969-79).
bFGF, known as a bone formation biomarker highly associated with osteoporosis, is reported to have no relation to fracture healing (Xu et al., Chin. J. Traumatol. 6, 160˜166, 2003).
For these reasons, currently available therapeutic agents for the treatment of osteoporosis are not adequate to apply to bone fractures. Therefore, there is an urgent need for a bone fracture curative that has great therapeutic effect on bone fractures, regardless of association with osteoporosis.
Leading to the present invention, intensive and thorough study on fracture healing, conducted by the present inventors, resulted in the finding that N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}-benzamidine and 4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}-benzamidine, developed as a medicament for the treatment of osteoporosis by the present inventors (Korean Pat. Unexamined Publication No. 10-2003-8654), can enhance the bone density and strength of the bony callus formed during a fracture healing process and promote endochondral ossification and intramembranous ossification in connective tissue, thereby exhibiting excellent healing effects on fractures, in spite of great differences between osteoporosis and fracture mechanisms.